Condensed pyridine compound

Abstract

The present invention provides a compound having excellent JAK3 inhibitory activity and being useful as an active ingredient of an agent for treating and/or preventing various immune diseases including autoimmune diseases, inflammatory diseases, and allergic diseases. As a result of investigations with respect to novel condensed heterocyclic derivatives, the inventors have verified that a condensed pyridine compound has excellent JAK3 inhibitory activity, thereby completing the present invention. More specifically, it has been verified that since the compound according to the present invention has inhibitory activity against JAK3, the compound is useful as an active ingredient of an agent for treating or preventing diseases caused by undesirable cytokine signal transduction (e.g., rejection during live organ/tissue transplantation, autoimmune diseases, asthma, atopic dermatitis, rheumatism, psoriasis and atherosclerotic disease), or diseases caused by abnormal cytokine signal transduction (e.g., cancer and leukemia).

1 . A condensed pyridine compound represented by following formula (I), pharmaceutically acceptable salts thereof, and prodrugs thereof: 
     
       
         
         
             
             
         
       
     
     wherein
 R 1  is —H or ═O; 
 R 3  is carbamoyl or oxadiazolyl,
 each of which is optionally substituted with C 1 -C 6  alkyl; 
 
 R 21  is —H or is optionally bonded with R 3  via a certain functional group to form divalent groups represented by following formulas (IA), (IB), (IC) or (ID): 
 
     
       
         
         
             
             
         
       
       R A  is —H or C 1 -C 6  alkyl; 
       R B  is —H or C 1 -C 6  alkyl; 
       R C  is —H, C 1 -C 6  alkyl or (C 1 -C 6  alkyl)-O—(C 1 -C 6  alkyl); 
       R D  is —H, —C(═O)—(C 1 -C 6  alkyl), —C(═O)—(C 1 -C 6  alkyl)-O—(C 1 -C 6  alkyl), —C(═O)C(═O)NH—(C 1 -C 6  alkyl), —C(═O)C(═O)NH—(C 1 -C 6  alkyl)-O—(C 1 -C 6  alkyl) or —C(═O)O-(alkyl); 
       R 22  is 5- to 7-membered nitrogen-containing
 heterocycloalkyl, C 3 -C 9  cycloalkyl, benzopyranyl or 
 benzyl, 
 each of which is optionally substituted with one or more identical or different group(s) selected from the group consisting of R V ; 
 
       R V  is halogen, C 1 -C 6  alkyl, —O—(C 1 -C 6  alkyl), aryl,
 5- to 6-membered nitrogen-containing heteroaryl, 
 benzyl, carbamoyl, —(C═O)—(C 1 -C 6  alkyl), 
 —C(═O)-(5- to 6-membered heteroaryl), —C(═O)-(5- to 6-membered nitrogen-containing heterocycloalkyl), —C(═O)-carbamoyl, —C(═O)C(═O)-(5- to 6-membered nitrogen-containing heterocycloalkyl), —C(═O)O—(C 1 -C 6  alkyl); 
 each of which is optionally substituted with one or more identical or different group(s) selected from the group consisting of R W ; 
 
       R W  is halogen, —CN, —CF 3 , —OH, ═O, —NO 2 , carbamoyl, oxime, C 1 -C 6  alkyl, —(C 1 -C 6  alkyl)-CN, —(C 1 -C 6  alkyl)-OH, —C(═O)O—(C 1 -C 6  alkyl), —O—(C 1 -C 6  alkyl), —O—(C 1 -C 6  alkyl)-CN, 2-pyrroridinone-1-yl or phenyl,
 wherein phenyl is optionally substituted with halogen; 
 
       Y is N, CH or CH 2 ; and 
          is a single bond or a double bond wherein one is single bond and the other is double bond. 
     
   
   
       2 . The compound of  claim 1  having following formula (II), pharmaceutically acceptable salts thereof, and prodrugs thereof: 
     
       
         
         
             
             
         
       
     
     wherein
 R 1  is —H or ═O; 
 R 3  is carbamoyl or oxadiazolyl,
 each of which is optionally substituted with C 1 -C 6  alkyl; 
 
 R 21  is —H or is optionally bonded with R 3  via a certain functional group to form divalent groups represented by following formula (IA): 
 
     
       
         
         
             
             
         
       
       R A  is —H or C 1 -C 6  alkyl; 
       R 4  is aryl, 5- to 6-membered heteroaryl,
 benzyl, carbamoyl, —C(═O)-(5- to 6-membered heteroaryl), —C(═O)-(5- to 6-membered nitrogen-containing heterocycloalkyl), —C(═O)-carbamoyl, —C(═O)C(═O)-(5- to 6-membered nitrogen-containing heterocycloalkyl), —C(═O)O—(C 1 -C 6  alkyl), each of which is optionally substituted with one or more identical or different group(s) selected from the group consisting of R 41 ; 
 
       R 41  is halogen, —CN, —CF 3 , —OH, ═O, —NO 2 , carbamoyl, oxime,
 C 1 -C 6  alkyl, —(C 1 -C 6  alkyl)-CN, —(C 1 -C 6  alkyl)-OH, —C(═O)O—(C 1 -C 6  alkyl), —O—(C 1 -C 6  alkyl), —O—(C 1 -C 6  alkyl)-CN, 2-pyrroridinone-1-yl or phenyl, 
 wherein phenyl is optionally substituted with halogen; 
 
       R 5  is halogen or —O—(C 1 -C 6  alkyl); 
       n is an integer from 1 to 6; 
       Y is N, CH or CH 2 ; and 
          is a single bond or a double bond wherein one is single bond, the other is double bond. 
     
   
   
       3 . The compound of  claim 2  represented by the formula (II), pharmaceutically acceptable salts thereof, and prodrugs thereof, wherein:
 R 4  is aryl or 5- to 6-membered nitrogen-containing heteroaryl,
 or —C(═O)O—(C 1 -C 6  alkyl), 
 each of which is optionally substituted with one or more identical or different group(s) selected from the group consisting of R 41 ; and 
   R 41  is halogen, —CN, —CF 3 , —CH 2 OH, —CONH 2 , —C(═O)O—(C 1 -C 6  alkyl) or —NO 2 .   
   
   
       4 . The compound of  claim 3  represented by the formula (II), pharmaceutically acceptable salts thereof, and prodrugs thereof, wherein:
 R 5  is halogen.   
   
   
       5 . The compound of  claim 4  represented by the formula (II), pharmaceutically acceptable salts thereof, and prodrugs thereof, wherein:
 R 3  is —CONH 2  or —C(═O)NH—(C 1 -C 6  alkyl);   Y is CH; and   R 1  is —H.   
   
   
       6 . The compound of  claim 5  represented by the formula (II), pharmaceutically acceptable salts thereof, and prodrugs thereof, comprising:
 (1) rel-4-{[(3R,4S)-1-(6-Cyanopyridazin-3-yl)-3-fluoropiperidin-4-yl]amino}-1H-pyrrolo[2,3-b]pyridine-5-carboxamide,   (2) rel-4-{[(3R,4S)-1-(5-Cyanopyridin-2-yl)-3-fluoropiperidin-4-yl]amino}-1H-pyrrolo[2,3-b]pyridine-5-carboxamide,   (3) Ethyl rel-(3R,4S)-4-[(5-carbamoyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino]-3-methoxypiperidine-1-carboxylate,   (4) rel-4-{[(3R,4R)-1-(5-Cyanopyridin-2-yl)-3-fluoropiperidin-4-yl]amino}-1H-pyrrolo[2,3-b]pyridine-5-carboxamide,   (5) rel-4-{[(3R,4S)-1-(5-Cyanopyridin-2-yl)-3-methoxypiperidin-4-yl]amino}-1H-pyrrolo[2,3-b]pyridine-5-carboxamide,   (6) rel-4-{[(3R,4S)-1-(5-Cyano-1,3-thiazol-2-yl)-3-fluoropiperidin-4-yl]amino}-1H-pyrrolo[2,3-b]pyridine-5-carboxamide,   (7) rel-4-({(3R,4S)-3-Fluoro-1-[6-(trifluoromethyl)pyridazin-3-yl]piperidin-4-yl}amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide,   (8) 4-{[1-(5-Cyanopyridin-2-yl)-3,3-difluoropiperidin-4-yl]amino}-1H-pyrrolo[2,3-b]pyridine-5-carboxamide,   (9) rel-6-[(3R,4S)-3-Fluoro-4-(2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)piperidin-1-yl]nicotinonitrile,   (10) 4-{[(3S,4R)-1-(5-Cyanopyridin-2-yl)-3-fluoropiperidin-4-yl]amino}-1H-pyrrolo[2,3-b]pyridine-5-carboxamide,   (11) 4-{[(3S,4R)-1-(6-Cyanopyridazin-3-yl)-3-fluoropiperidin-4-yl]amino}-1H-pyrrolo[2,3-b]pyridine-5-carboxamide,   (12) 4-{[(3R,4S)-1-(6-Cyanopyridazin-3-yl)-3-fluoropiperidin-4-yl]amino}-1H-pyrrolo[2,3-b]pyridine-5-carboxamide,   (13) 4-{[(3R,4S)-1-(4-Cyanophenyl)-3-fluoropiperidin-4-yl]amino}-1H-pyrrolo[2,3-b]pyridine-5-carboxamide,
 and 
   (14) rel-6-[(3R,4S)-3-Fluoro-4-(2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)piperidin-1-yl]nicotinonitrile.   
   
   
       7 . The compound of  claim 1  having following formula (III), pharmaceutically acceptable salts thereof, and prodrugs thereof: 
     
       
         
         
             
             
         
       
     
     wherein
 R 3  is carbamoyl or oxadiazolyl,
 each of which is optionally substituted with C 1 -C 6  alkyl; 
 
 R 21  is —H or is optionally bonded with R 3  via a certain functional group to form divalent groups represented by following formula (IA): 
 
     
       
         
         
             
             
         
       
       R A  is —H or C 1 -C 6  alkyl; 
       R 4  is aryl, 5- to 6-membered heteroaryl, benzyl, carbamoyl,
 —(C═O)—(C 1 -C 6  alkyl), —C(═O)-(5- to 6-membered heteroaryl), —C(═O)-(5- to 6-membered nitrogen-containing heterocycloalkyl), —C(═O)-carbamoyl, —C(═O)C(═O)-(5- to 6-membered nitrogen-containing heterocycloalkyl), —C(═O)O—(C 1 -C 6  alkyl), each of which may be substituted with one or more identical or different group(s) selected from the group consisting of R 41 ; and 
 
       R 41  is halogen, —CN, —CF 3 , —OH, ═O, —NO 2 , carbamoyl, oxime, C 1 -C 6  alkyl, —(C 1 -C 6  alkyl)-CN, —(C 1 -C 6  alkyl)-OH, —C(═O)O—(C 1 -C 6  alkyl), —O—(C 1 -C 6  alkyl), —O—(C 1 -C 6  alkyl)-CN, 2-pyrroridinone-1-yl or phenyl,
 wherein phenyl is optionally substituted with halogen. 
 
     
   
   
       8 . The compound of  claim 7  having the formula (III), pharmaceutically acceptable salts thereof, and prodrugs thereof, wherein:
 R 3  is —CONH 2  or —C(═O)NH—(C 1 -C 6  alkyl).   
   
   
       9 . The compound of  claim 8  having the formula (III), pharmaceutically acceptable salts thereof, and prodrugs thereof, comprising
 7-{[1-(5-Cyanopyridin-2-yl)azepan-4-yl]amino}-3H-imidazo[4,5-b]pyridine-6-carboxamide.   
   
   
       10 . The compound of  claim 1  having following formula (IV), pharmaceutically acceptable salts thereof, and prodrugs thereof: 
     
       
         
         
             
             
         
       
     
     wherein
 R 1  is —H or ═O; 
 R 21  is bonded with R 3  via a certain functional group
 to form divalent groups represented by following formula (IB), (IC) or (ID): 
 
 
     
       
         
         
             
             
         
       
       R B  is —H or C 1 -C 6  alkyl; 
       R C  is —H, C 1 -C 6  alkyl or (C 1 -C 6  alkyl)-O—(C 1 -C 6  alkyl); 
       R D  is —H, —C(═O)—(C 1 -C 6  alkyl), —C(═O)—(C 1 -C 6  alkyl)-O—(C 1 -C 6  alkyl), —C(═O)C(═O)NH—(C 1 -C 6  alkyl), —C(═O)C(═O)NH—(C 1 -C 6  alkyl)-O—(C 1 -C 6  alkyl) or —C(═O)O-(alkyl); 
       R 22  is 5- to 7-membered nitrogen-containing heterocycloalkyl,
 C 3 -C 9  cycloalkyl, or benzyl, 
 each of which is optionally substituted with one or more identical or different group(s) selected from the group consisting of R V1 ; 
 
       R V1  is halogen, C 1 -C 6  alkyl, —O—(C 1 -C 6  alkyl), aryl,
 5- to 6-membered heteroaryl, —(C═O)—(C 1 -C 6  alkyl), —(C═O)-(5- to 6-membered nitrogen-containing heterocycloalkyl), —(C═O)O—(C 1 -C 6  alkyl), or carbamoyl, each of which may be substituted with one or more identical or different group(s) selected from the group consisting of R W1 ; 
 
       R W1  is halogen, —CN, —CF 3 , —OH, ═O, —NO 2 , carbamoyl, oxime,
 C 1 -C 6  alkyl, —(C 1 -C 6  alkyl)-CN, —(C 1 -C 6  alkyl)-OH, —C(═O)O—(C 1 -C 6  alkyl), —O—(C 1 -C 6  alkyl), —O—(C 1 -C 6  alkyl)-CN, 2-pyrroridinone-1-yl or phenyl, 
 wherein phenyl is optionally substituted with halogen; 
 
       X is N, CH or CH 2 ; and 
          is a single bond or a double bond,
 wherein one is single bond, the other is double bond.   
     
   
   
       11 . The compound of  claim 10  having the formula (IV), pharmaceutically acceptable salts thereof, and prodrugs thereof, wherein
 Y is CH;   R 1  is —H;   R 21  and R 3  form a group of represented by the formula (ID);   R D  is —H or —C(═O)C(═O)NH—(C 1 -C 6  alkyl); and   R 22  is 5- to 7-membered nitrogen-containing heterocycloalkyl or
 C 3 -C 9  cycloalkyl, 
 each of which is optionally substituted with one or more identical or different group(s) selected from the group consisting of R V1 . 
   
   
   
       12 . The compound of  claim 11  having the formula (IV), pharmaceutically acceptable salts thereof, and prodrugs thereof,
 which is selected from the group consisting of:   (1) rel-(2R,4R)-4-fluoro-1-{[(3S,4S)-4-methyl-3-(2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)piperidin-1-yl]carbonyl}pyrrolidine-2-carbonitrile,   (2) rel-3-[(3R,4R)-3-(3-aminopyrazolo[3,4-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-4-methylpiperidin-1-yl]-3-oxopropanenitrile,   (3) rel-3-[(3R,4R)-4-methyl-3-(3-oxo-3,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)piperidin-1-yl]-3-oxopropanenitrile,   (4) rel-N-{1-[(3R,4R)-1-(cyanoacetyl)-4-methylpiperidin-3-yl]-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridin-3-yl}-N′-(cyclopropylmethyl)ethanediamide,   (5) rel-6-[(3R,4R)-3-(3-aminopyrazolo[3,4-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-4-methylpiperidin-1-yl]pyridazine-3-carbonitrile,   (6) rel-N-{1-[(3R,4R)-1-(5-cyanopyridin-2-yl)-4-methylpiperidin-3-yl]-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridin-3-yl}-N′-(cyclopropylmethyl)ethanediamide,   (7) rel-N-(1-{(3R,4R)-1-[(cyanomethyl)(methyl)carbamoyl]-4-methylpiperidin-3-yl}-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridin-3-yl)—N′-isopropylethanediamide, and   (8) rel-N-(1-{(3R,4R)-1-[(cyanomethyl)(methyl)carbamoyl]-4-methylpiperidin-3-yl}-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridin-3-yl)—N′-(cyclopropylmethyl)ethanediamide.   
   
   
       13 - 14 . (canceled) 
   
   
       15 . A medicament comprising the compound according to  claim 1  as an active ingredient. 
   
   
       16 . A medicament comprising the compound according to  claim 1  as an active ingredient, with a pharmaceutically acceptable carrier or excipient. 
   
   
       17 . A janus kinase 3 (JAK3) inhibitor comprising the compound according to  claim 1 . 
   
   
       18 . A method for treating and/or preventing diseases comprising rejection during organ/tissue transplantation, autoimmune diseases, multiple sclerosis, rheumatoid arthritis, psoriasis, asthma, atopy, tumors, plasmacytic myeloma and leukemia in human beings or animals, said method comprising administrating the compound according to  claim 1  to human beings or animals. 
   
   
       19 . (canceled) 
   
   
       20 . A product comprising a pharmaceutical composition comprising the compound according to  claim 1 . 
   
   
       21 . The compound of  claim 1  represented by the formula (I). 
   
   
       22 . The compound of  claim 1 , which is a pharmaceutically acceptable salt of formula (I) 
   
   
       23 . The compound of  claim 1 , which is a prodrug of formula (I)